- The goal of the proposed studies is to develop a better understanding of the biological role of a novel epithelial-specific transcription factor designated ESE-1 which is a member of the Ets transcription factor/oncogene family, during epithelial cell differentiation. A primary human keratinocyte differentiation system will be used as a model for one type of epithelial cell differentiation. Normal function of keratinocytes requires proper differentiation along a tightly controlled developmental pathway resulting in cell cycle arrest and eventually apoptosis. Particular stages of keratinocyte differentiation are characterized by tightly regulated expression of certain sets of genes. The stringent control is at least partially due to transcriptional regulation by distinct sEts of transcription factors. Deregulated expression of Ets factors has been directly implicated in aberrant cell differentiation and human cancer indicating that unraveling the normal function of a transcription factor may help to explain its role in carcinogenesis. The applicant has recently isolated a novel member of the Ets family, ESE-1, with features distinct from any other Ets- related factor. ESE-1 contains two putative DNA binding domains, a unique Ets domain and two A/T-hook domains found in HMG proteins and various other nuclear factors. In contrast to any known Ets factors, ESE-1 is exclusively expressed in epithelial cells. ESE-1 is not expressed in undifferentiated primary human keratinocytes, but expression is highly inducible upon differentiation. Since forced expression of ESE-1 in undifferentiated keratinocytes inhibits keratinocyte growth, the applicant hypothesizes that ESE-1 is involved in induction of cell cycle arrest or terminal differentiation in epithelial cells. The aim of the proposal is to evaluate the role of ESE-1 in keratinocytes and during mouse development. Thus the specific aims are: (i) Define the function of different structural domains of ESE-1, (ii) determine the role of ESE-1 in the regulation of keratinocyte specific SPRR2A gene expression, and (iii) examine the effect of ESE-1 expression on keratinocytes. Due to the importance of the Ets family in regulation of various tissue and differentiation-specific genes, ESE-1 is expected to play a central role in keratinocyte differentiation in particular and in epithelial cell differentiation in general. It is believed that elucidation of the function of ESE-1 in modulating keratinocyte differentiation or proliferation will provide exciting opportunities to test the hypothesis that altered functions of this Ets factor result in carcinomas.